Project Summary/Abstract The detailed study of the chemistry and biology of complex natural products at a fundamental level provides critical insight to understanding their mode of action and enables development of new approaches for treatment of various human ailments. This research program focuses on the development of efficient and concise total chemical syntheses of structurally complex and biologically active natural products through the systematic discovery, development, and application of new synthetic strategies and methodologies. The targets are selected based on novelty of molecular architecture, paucity of prior synthetic studies, abundance of opportunities for development of new strategies and methodologies, possession of significant biological activity, and the potential for future chemical and biological studies. This program will focus on synthetic studies of the rich family of cyclotryptamine and diketopiperazine alkaloids. Of central interest is the directed, regioselective, stereoselective, and efficient union of cyclotryptamine substructures providing late-stage couplings to secure challenging linkages, including complete stereocontrol at quaternary stereogenic centers. Convergent and guided assembly of advanced fragments is complemented by application of new highly selective transformations for the rapid generation of molecular complexity. These include stereoretentive diketopiperazine hydroxylation followed by stereocontrolled sulfidation, employing a variety of new reagents and conditions developed in this program, to access the corresponding epipolythiodiketopiperazines. With this program's access to potently bioactive families of complex alkaloids and derivatives, we look for opportunities for extensive comparative analysis of groups of compounds to gain valuable insight concerning structure-activity relationships that can inform synthesis of designed derivatives to facilitate further biochemical collaborative investigations. This program will continue to provide synthetic samples of rare and precious compounds for structure validation and detailed examination of their chemistry and biology. The well recognized biological activity of this rich family of alkaloids ensure that the many related intermediates and derivatives accessed through these efforts will also behold great promise both as mechanistic tools and as new bioactive compounds, and thus they will be subject to continuous evaluation through our multidisciplinary and collaborative engagements.